This project will test alternative models regarding the impacts of infectious disease and inflammation on cardiovascular disease and diabetes. Over a decade of research on Tsimane forager-horticulturalists of Bolivia has revealed high rates of inflammation throughout life due to multiple infectious processes. Given that inflammation is causally involved in atherosclerosis and predicts risk of myocardial infarction and stroke, it is striking that we find among Tsimane minimal hypertension, a near absence of infarcts, improved diastolic function relative to age-matched Westerners, low incidence of diabetes, and low serum lipid levels, particularly LDLs. This project will synthesize 10+ years of panel data to address why Tsimane cardiovascular function remains well-preserved and why diabetes risk remains low throughout adulthood. There are three specific aims of this R01 renewal application. Aim 1 completes analyses of stored biological specimens (serum, urine, feces) and cardiovascular data (e.g. ultrasonographic, tonometric) collected over the last decade. Aim 2 conducts heritability analyses on cardiometabolic and immune-related traits using genealogically derived pedigrees, to control for effects of heritable variation and to assess whether these traits share common influences. Aim 3 tests hypotheses derived from alternative models of infection, immune regulation, cardiovascular disease and diabetes, which include examining the relative importance of lifestyle factors (e.g. diet, physical activity level), heritability and their interations. The Tsimane provide a unique opportunity to study arterial, heart and metabolic health in a pre-industrial population with high infectious load but with limited food intake and high physical activity throughout life. We will employ integrated longitudinal epidemiological, demographic and anthropological methodologies that are directly comparable to methods employed in other countries, including measurement of immune responses (in vivo and in vitro), histology, ultrasound imaging, and arterial tonometry. We will also be able to examine effects of acculturation on communicable and non-communicable disease processes, at community, family, and individual levels. We will compare our results to those obtained in the U.S. and other countries, to assess the relative impacts of infection, inflammation, lifestyle, and heritability o cardiovascular and metabolic health over the life course.